Use of cesium as a stimulant in mammals

ABSTRACT

THE USE OF THE CESIUM ION AS A STIMULANT IN MAMMALS IS DISCLOSED WHERE THE CESIUM IS ADMINISTERED AS AN ORGANIC OR INORGANIC SALT AT A LEVEL SUFFICIENT TO OBTAIN A DOSE OF FROM 0.1 TO 5.0 MILLIEQUIVALENTS OF CESIUM PER KILOGRAM OF BODY WEIGHT OF THE MAMMAL AND TO ESTABLISH A BLOOD SERUM LEVEL OF ABOUT 0.05 MILLIEQUIVALENT OF CESIUM PER LITER.

United States Patent 3,641,242 USE OF CESIUM AS A STIMULANT IN MAMMALS Howard L. Masco, Glen Mills, Pa., assiguor to Atlas Chemical Industries, Inc., Wilmington, Del. N0 Drawing. Filed Apr. 13, 1970, Ser. No. 28,070

Int. Cl. A61k 27/00 U.S. Cl. 424-153 8 Claims ABSTRACT OF THE DISCLOSURE The use of the cesium ion as a stimulant in mammals is disclosed where the cesium is administered as an organic or inorganic salt at a level sufiicient to obtain a dose of from 0.1 to 5.0 milliequivalents of cesium per "kilogram of body weight of the mammal and to establish a blood serum levelof about 0.05 milliequivalent of cesium per liter.

This invention relates to the use of the cesium ion as a stimulant in mammals. More particularly, it involves the process of administering cesium as a salt to mammals by oral or parenteral administration.

It is known in the art that various chemicals such as the tricyclics e.g. imipramine; MAO inhibitors, e.g. isocarboxazid; and other compounds which act as stimulants cause an increase in physical activity which may be related to an increase in the overall level of body functions of a stimulation of particular parts of the body such as cerebral stimulation, cardiac stimulation or muscular stimulation. The exact mechanism by which these drugs increase the activity of the subjects is not well understood. However, those drugs which have been found to increase the activity of lower mammals such as mice, rats, rabbits, and dogs, have also been found to work as anti-depressants and/or stimulants in higher mammals and man. Thus a correlation between increased activity and anti-depressant or stimulant function appears to exist. One of the factors which makes any particular anti-depressant useful is the ease' of administration, because it allows its use over a long period of time without constant medical attention. It has. been previously determined that the lithium ion when administered in the form of a salt acts as a depressant in mammals and manic or hypomanic humans; the mechanism probably involves transmembrane potentials in the nervous system. We have discovered, in accordance with this invention, that the cesium ion exhibits an opposite effect than that of lithium and is a stimulant.

It is an object of this invention to provide a process for administering the cesium ion to mammals by oral ingestion of cesium salt.

Another object of this invention is to provide a process for producing increased physical activity in mammals by the administration of cesium ion as its salt.

The above and still other objects of this invention will become apparent to those skilled in the art from the following detailed description of the invention.

It has been discovered that the cesium ion at the proper concentration will cause an increased activity in mammals; more particularly, an increase in activity will occur when cesium ion is administered as a salt so that the cesium ion in vivo concentration is at least about 0.05 milliequivalent per liter of blood serum, and preferable at a concentration of from about 0.2 to about 2.0 milliequivalents per liter. The above minimum concentration is usually needed to achieve a response in the subject mammal. The cesium salt is given at a dose level of from about 0.1 to about 5.0 milliequivalents per kilogram of body weight (KGBW) of the mammal. At a dose of less than about 0.1 milliequivalent, the serum level increases slowly which may cause a long time interval before an effect is seen; at dose levels above about 5.0 milliequivalents/KGBW the salt may be toxic. A preferred dose level for a cesium salt is the administration of sufficient cesium salt to achieve from 0.4 to 1.0 milliequivalent of cesium ion per KGBW.

The cesium may be administered as an organic or inorganic salt and as such may be given as a solution, as a powder, as a tablet or as a capsule. Naturally a binder and flavoring ingredients may be added as needed. The cesium salt may be administered orally or parenterally. Once a dose rate is found which causes the desired increase in physical activity, the subject may be fed the salt as part of his diet, thereby maintaining the effect of the cesium ion. The cesium is usually given only once per day although smaller doses given a few times a day will work.

Although almost any salt of cesium can be used to obtain a cesium ion level of the proper dosage in the body of the subject mammal the salt should be essentially water soluble and the anion of the salt should not be toxic at the levels reached in administering the cesium. It has been found that cesium carbonate, cesium bicarbonate, cesium chloride, cesium bitartrate, cesium sulfate, cesium iodide, cesium bisulfate, cesium proprionate, cesium acetate, and cesium citrate work well. Within the above list of salts those which cause minimal irritation when administered by injection or orally include the carbonate, bicarbonate, citrate, chloride, and bitartrate salts of cesium. The preferred inorganic salts of cesium are the carbonate, chloride and bicarbonate.

The increase in spontaneous activity may be observed with a single administration. However, administration over a longer period, as for example three days, may be needed in many cases. To show a quantitative increase in the activity of the subject mammals after ingestion of the cesium, an activity cage is used. The activity cage is a standard laboratory cage which is equipped with photoelectric cells. The cells register counts on an electronic counter when a light beam is broken. Thus an animal, e.g., a mouse, moving around the cage breaks the beams and causes a count to be made of his activity; the greater the activity of the animal the greater the number of times the light beams are broken. This count is thus directly related to the locomotive activity of the animal as it moves around the cage. Therefore, an activity cage allows a record of an animals motor activity to be made and of the increase or decrease in activity determined by following the number of counts in a given time period. A commercially available activity cage is the Lehigh Valley activity cage.

The following example of determining an increase in activity in mice of the MF-l strain obtained from Manor Farms in Statsberg, N.Y., after administration of cesium, illustrates the instant invention.

EXAMPLE 1 Groups of three male mice, weighing between 20 and 25 grams, were selected randomly from a colony of mice. To a group of three male mice, an aqueous solution of cesium carbonate is administered 'by oral injection. The concentration of the aqueous solution is 6.9 mg./cc. A single 0.25 ml. dose, 0.6 milliequivalent of cesium per kilogram of body weight, is administered to each mouse for nine consecutive days. After the ninth dose the mice are placed in a Lehigh Valley activity cage and their activity is measured over an hour period, summing the counts for each five minute interval.

A second group of three mice are given oral injections of an 0.9% NaCl solution in 0.25 ml. doses, 1.5 milliequivalents of NaCl per kilogram of body Weight, for five consecutive days. The activity of these mice is similarly measured for an hour period, summing the counts at 5 minute intervals.

A third group of three mice are given oral injections of an 0.9% NaCl solution in 0.25 ml. doses for five consecutive days at which time they are injected intraperitoneally with reserpine, a tranquilizer, at a 10 mg./ kg. dose rate. The activity of these mice is similarly measured for an hour period, summing counts at minute intervals.

The count data for the mice given the cesium, the NaCl and the reserpine is given in Table I. Because of the initial curiosity after being placed in the cage all three sets are active in the first interval. However, as the hour period progresses the cesium intubated mice retain a high level of activity compared to the NaCl control and the effect of the reserpine is evident in the third set of mice. At the end of the hour the cesium fed mice have been almost twice as active as the control mice and the reserpine mice less than /2 as active as the control mice.

To further illustrate the instant invention the following is an example of the effect of cesium when orally injected into rats.

EXAMPLE 2 Six male rats are randomly selected from a colony of Wistar MW3(SPF) rats. These rats are found to weigh from 180-200 grams.

Four rats are orally given cesium carbonate solution at a concentration of 22.08 milligrams per 1 cc. of solution at a dose level of 0.5 ml. per day for five consecutive days, this equals 0.6 milliequivalent of cesium per kilogram of body weight per day. The activity of these four rats is then measured by placing two rats in each of two Lehigh Valley activity cages for an hour period and summing the counts for each five minute interval.

The two remaining rats are orally fed a 0.9% NaCl solution at a dose level of 0.5 ml. per day which equals 0.4 milliequivalent of NaCl per kilogram of body weight for five consecutive days. The activity of these rats is similarly measured.

The activity increase is from 50 to 100% over the NaCl control for the cesium treated rats, when the total counts for an hour are compared as illustrated in Table I.

TABLE I Lehigh Valley photoelectric activity cage levels Counts Mice Rats Time Cesium Cesium interval] carbon- Sodium Resercarbon- Sodium Reserminutes ate chloride pine ate chloride pine The data in Table I firmly establishes that cesium is a stimulant in mammals, causing a marked increase in overall level of motor activity. The correlation of this type of response with an anti-depressant and/or stimulant activity of the chemical in mammals is well established as stated supra.

Having thus described the invention the following is claimed:

1. A process for stimulating mammals which comprises administering a cesium salt to a mammal in need of such stimulation at a sufficient level to effect said stimulation and in such a quantity to establish a blood serum level of at least 0.05 milliequivalents of cesium ion per liter of blood serum.

2. A process for stimulating mammals according to claim 1 wherein said cesium salt is selected from the group consisting of cesium carbonate, cesium bicarbonate, cesium chloride, cesium bitartrate, cesium sulfate, cesium iodide, cesium bisulfate, cesium acetate, cesium citrate and cesium propionate.

3. A process for stimulating mammals according to claim 1 wherein said salt is selected from the group consisting of cesium carbonate, cesium bicarbonate, cesium citrate, cesium chloride, and cesium bitartrate.

4. A process for stimulating mammals according to claim 1 wherein said cesium salt is an inorganic salt selected from the group consisting of cesium carbonate, cesium chloride, and cesium bicarbonate.

5. A process for stimulating mammals according to claim 1 wherein said cesium salt is administered in sufiicient quantity to achieve a dose level of from 0.1 to' 5 milliequivalent per kilogram of body weight.

6. A process for stimulating mammals according to claim 2 wherein said cesium salt is administered in such a quantity to establish a cesium ion blood serum level of from 0.2 to 2.0 milliequivalents per kilogram of body weight and which is administered at a dose level of from 0.4 to 1.0 milliequivalents per kilogram of body weight.

7. A process for simulating mammals according to claim 3 wherein said cesium salt is administered at such a level as to achieve a dose level of from .4 to 1 milliequivalent of cesium per kilogram of body weight.

8. A process for stimulating mammals according to claim 4 wherein said cesium salt is administered in sulficient quantity to achieve a dose level of from 0.4 to 1 milliequivalent of cesium per kilogram of body weight.

References Cited Lancet, II, No. 7561, July 27, 1968, p. 216. Chem. Abst., 52, 20268C (1958).

STANLEY J. FRIEDMAN, Primary Examiner US. Cl. X.R. 424162, 317

y UNI EDSTATEMKTENT651C11 I w M 7 CERTIFICATE OF CORRECTIGN Patent No. 3,641,242 Da February 8 1972 It is certified that error appears inuthe above-identified patent and that said Letters Patent are hereby corrected as shown below:

. Y "1 Column 3, Table ,I, under the heading "Rats" the two columns beginning, with the numbers "663" and "455" should all be under the heading "Cesium carbonate." The third column of figures beginning with the number "535" should beunder the heading "Sodium chloride" and the heading "Reserpine" should be deleted altogether.

Column 4 Claim 7, line 39 the word "simulating" should read stimulating Signed and sealed this 2nd day of January 1973.

(SEAL) Attest;

1 EDWARD M,FLET( JHER,JR. ROBERT GOTTSGHALK Attesting Officer Commissioner: of Patents 

